Year: 2025
Type: article
Abstract: Endogenous uridine-rich small nuclear RNAs (U snRNAs) form RNA-protein complexes to process eukaryotic pre-mRNA into mRNA. Previous studies have demonstrated programmable U snRNA guide-targeted exon inclusion and exclusion. Here we investigated whether snRNAs can also enhance RNA base editing over state-of-the-art RNA-targeting technologies in human cells. Compared with adenosine deaminase acting on RNA (ADAR)-recruiting circular RNAs, we find that guided A>I snRNAs consistently increase adenosine-to-inosine editing for higher exon count genes, perturb substantially fewer off-target genes and localize more persistently to the nucleus where ADAR is expressed. A>I snRNAs also more efficiently edit long noncoding RNAs and pre-mRNA 3' splice sites to promote splicing changes. Lastly, snRNA-H/ACA box snoRNA fusions (U>Ψ snRNAs) increase targeted RNA pseudouridylation without DKC1 overexpression, facilitating improved CFTR rescue from nonsense-mediated mRNA decay in a cystic fibrosis human bronchial epithelial cell model. Our results advance the endogenous protein-mediated RNA base editing toolbox and RNA-targeting technologies to treat genetic diseases.
Source: Nature Chemical Biology
Authors: Aaron A. Smargon, Deepak Pant, Trent A. Gomberg, Christian Fagre, Sofia Glynne, Johnathan Nguyen, Jack T. Naritomi, Wendy V. Gilbert, Gene W. Yeo
Language: English
Topic: RNA regulation and disease
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W4414335915